Abstract
Type I interferons (IFNs) are produced by most cells in response to virus infection and stimulate a program of anti-viral gene expression in neighboring cells to suppress virus replication. Type III IFNs have similar properties, however their effects are limited to epithelial cells at mucosal surfaces due to restricted expression of the type III IFN receptor. Rotavirus (RV) replicates in intestinal epithelial cells that respond predominantly to type III IFNs, and it has been shown that type III rather than type I IFNs are important for controlling RV infections in vivo. The RV NSP1 protein antagonizes the host type I IFN response by targeting IRF-3, IRF-5, IRF-7, or β-TrCP for proteasome-mediated degradation in a strain-specific manner. Here we provide the first demonstration that NSP1 proteins from several human and animal RV strains antagonize type III as well as type I IFN induction. We also show that NSP1 is a potent inhibitor of IRF-1, a previously undescribed property of NSP1 which is conserved among human and animal RVs. Interestingly, all NSP1 proteins were substantially more effective inhibitors of IRF-1 than either IRF-3 or IRF-7 which has significance for evasion of basal anti-viral immunity and type III IFN induction in the intestinal epithelium.
Highlights
Published: 31 March 2021Rotaviruses (RVs) are members of the Rotavirus genus, one of 16 genera of the Reoviridae family that are grouped into at least 9 distinct species, named RVA-RVJ
This correlates with the greater effectiveness of these NSP1 proteins at inhibiting IFN Regulatory Factor (IRF)-3 in the luciferase assays compared to the human RVA NSP1s, this correlation does not hold for RRV NSP1 which is as effective as P343 and UKtc in the luciferase assays but does not interact with IRF-3 in yeast
Consistent with this study, we found evidence that IRF-1 is degraded in cells expressing NSP1, suggesting that the mechanism of inhibition of IRF-1 is distinct from the mechanism of inhibition of IRF-3, IRF-7 and IRF-9
Summary
Rotaviruses (RVs) are members of the Rotavirus genus, one of 16 genera of the Reoviridae family that are grouped into at least 9 distinct species, named RVA-RVJ (reviewed in [1]). NSP1 from several bovine, murine, and simian RVA strains interact directly with IRF-3 and promotes its degradation via the proteasome, preventing transcription of IFN-β [17,18,21]. NSP1s that bind IRF-3 contain the motif pLxIS (where p is a hydrophilic residue and x is any amino acid) found in MAVS, TRIF, and STING, the adapter proteins downstream of RLRs, TLRs, and the DNA sensor cGAS respectively, that recruit IRF-3 into signaling complexes [28]. Disruption of Jak/STAT signaling downstream of the type I IFN receptor is achieved by NSP1 through inhibition of STAT1/2 phosphorylation and nuclear import [34,35] The sum of these interactions is likely to have a critical impact on the ability of the host to control virus replication. TDO media but no growth on QDO media, ‘++’ indicates growth on QDO media, and ‘−‘ indicates no growth on either selection medium (i.e., no interaction)
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